A "growth factor" is about twenty small proteins that attach to specific receptors on the surface of stem cells in bone marrow and promote differentiation and maturation of these cells into morphotic constituents of blood. And blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction. If pharmaceutical EPO stimulates the bone marrow to make red blood cells, it could feed the growth of tumors in cancer patients.

A metastasis occurs when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs. This is the main cause of cancer death. For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives a signal from outside the cell. This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation.

The growth factor attaches to a receptor on the cell wall, initiating a sequence of changes in the cellular structure. The cell's internal skeleton - an assembly of densely-packed protein fibers - comes apart and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, a number of protein levels change: some get produced in higher quantities and some in less.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a map is needed all of the genetic changes that take place in the cell after the growth factor signal is received. One family of proteins stands out. Tensins are proteins that stabilize the cell structure. The amounts of one family member rise dramatically while, at the same time, the levels of another drop.

Despite a familial similarity, there is a significant difference between them. The protein that drops off has two arms: One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane. This action is what stabilizes the cell's structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than structural support, this protein acts as a kind of plug, blocking the anchor point, and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move, and, if it's a cancer cell, to metastasize to a new site in the body.

In experiments with genetically engineered cells, scientists have showed that the growth factor directly influences levels of both proteins, and that these, in turn, control the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration.

Scientists at The Weizmann Institute of Science, Rehovot, Israel, carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the 'plug' protein. High levels of this protein, in turn, were associated with cancer metastasis to the lymph nodes -- the first station of migrating cancer cells as they spread to other parts of the body.

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. The mechanism can predict the development of metastasis and possibly how the cancer will respond to treatment. This discovery may, in the future, aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.

Source: Weizmann Institute of Science

Roz

11-02-2007, 10:36 PM

Wouldn't that be wonderful? If not for us, definitely for those who are still to be diagnosed with metastatic IBC. (BUT I HOPE FOR US AS WELL!!)

sarah

11-03-2007, 02:37 AM

What drugs did they use? and are they available or not?
here's the quote from the article:
"In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells."

gdpawel

11-10-2007, 03:15 PM

On most cancer message/discussion boards, one of the most common themes is that of "chasing mets" (metatasis). Cancer patients are chasing mets because of the wrong type of chemotherapeutic regimens for their type of cancer histology. But why do patients with histologically similar tumors respond differently to so-called "standard" drug treatments? That is one of the main problems associated with chemotherapy. Patient tumors with the same histology do not necessarily respond identically to the same agent or dose schedule of multiple agents.

Medical oncologists select a drug and must wait to see whether it is effective on a particular patient. Conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. And when patients develop metastatic cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. For many cancers, especially after a relapse, more than one standard treatment exists.

A chemoresponse assay is a diagnostic test (not a treatment) to help measure the "efficacy" of cancer drugs. They cannot make the cancer drugs do better, it can only measure the "best" probability of successful drugs. This is in stark contrast to "standard" or "empiric" therapy (also called physician's choice therapy), in which chemotherapy for a specific patient is based on results from prior clinical studies.

Laboratory screening of samples from a patient's tumor (if available) can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents. It can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient. This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free and overall survival.

It would be highly desirable to know what drugs are effective against particular cancer cells before cytotoxic agents are systemcially administered into the body. Chemresponse assays are clinically validated drug tests on living (fresh) specimens of cancer cells to determine the optimal combination of chemotherapy drugs. These assays are specifically tailored for each individual patient based on tumor tissue profiling, with no economic ties to outside healthcare organizations, and recommendations are made without financial or scientific prejudice.

Recommendations are designed scientifically for each individual patient. Various assays are performed on a tumor sample to measure drug activity (sensitivity and resistance). This will determine not only what drug or combinations of drugs will not effectively work, but which will be most effective for an "individual's" cancer. Then a treatment recommendation is developed through what is known as "assay-directed" therapy.

2nd, 3rd, even 4th line therapies (why?)

I often read on the discussion boards about oncologists telling patients "if this drug doesn't work, we'll try this drug." And "if that drug doesn't work, we'll try this drug." In patients who have failed two, three or even four chemo drugs, why not give them the "right" drug or combinations the "first" time around?

In academic centers, patients are entered into clinical trials of square peg in a round hole therapy. This encourages the patient to receive 2nd, 3rd, and 4th line chemotherapy, regardless of the likelihood of meaningful benefit. The therapies are equivalent on a "population" basis, but not on an "individual" basis.

They continue to try and mate a notoriously heterogeneous disease into "one-size-fits-all" treatments. They predominately devote their clinical trial resources into trying to identify the best treatment for the "average" patient, in the face of evidence that this approach is non-productive.

According to NCI's official cancer information website on "state of the art" chemotherapy in recurrent or metastatic cancer, no data support the superiority of any particular regimen. There is no proven "standard" first line therapy which has been shown to be superior to the many other choices which exist.

The same situation exists in the setting of 2nd, 3rd, and 4th line therapy. Proven by the large number of patients who have progressive disease on 1st line therapy but who have good responses to 2nd or 3rd line therapy.

So it would appear that published reports of clinical trials provide precious little in the way of guidance. These patients patients should have received the "correct" treatment in the first line setting. This can be accomplished by individualizing cancer treatment based on testing the cancer biology.
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sarah

12-26-2007, 09:55 AM

thanks
sarah

Lani

12-28-2007, 11:25 AM

but growth factor receptors is a generic term that can include her2

Usually if they are referring to EGFR aka her1 they specify that rather than referring to the more general term "growth factor receptors" of which there are many

gdpawel

12-28-2007, 12:21 PM

Endothelial growth factor (EGF) is an important activator of angiogenesis. EGF causes endothelial cells to grow. Research has shown that oncogenes (genes that help cancer cells grow), cytokines (substances produced by the immune system), and hypoxia (a low-oxygen environment, which is common in tissues around solid tumors) can all directly or indirectly activate EGF, thereby starting angiogenesis.

EGF causes angiogenesis by attaching to special receptors (proteins on the outside of cancer cells that act like doorways), and this action starts a series of chemical reactions inside the cell. Because EGF is so important to angiogenesis, it is a target of new cancer treatments. For example, the drug bevacizumab (Avastin) blocks a receptor for EGF.

In addition to EGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to EGF, VEGF being one of them. Endostatin is a protein that talc stimulates healthy cells to produce after placed into the chest cavity during thoracoscopy, to inhibit the growth of tumors by cutting the flow of blood to metastatic lung tumors.

Avastin can be tested with a EGFR biomarker assay because the "target" of Avastin is not the cells themselves, but rather the hormone (VEGF) secreted by the tumor cells. Avastin complexes with free VEGF and blocks its action.

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Avastin is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are substances made in the laboratory that recognize and then attach to specific proteins on the outside of cancer cells. They may be used to stimulate the immune system to attack cancer cells or to deliver radiation, chemotherapy, or other biologic therapies more directly to a tumor.

Avastin directly binds to the protein VEGF, which spurs the growth of blood vessels. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis (microvasculature regression). Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. VEGF can cut off the supply of vessels that spring up to feed a tumor, but there is some uncertainty how Avastin works, or if it can get "inside" a cell.

And here's another possible indication. Scientists from the University of Innsbruck, Austria determined (via immunohistochemical staining for VEGF) that patients with Carcinomatous Meningitis (Leptomeningeal Carcinomatous) from breast cancer, significant amounts of VEGF are released into the cerebrospinal fluid (CSF). VEGF in CSF may be a useful biologic marker not only for the diagnosis but also the evaluation of treatment response in Carcinomatous Meningitis.

With respect to the metastasis, it is literally a cancer that has moved. It may have mutated further (cancer is itself a mutation that occurs within a cell that was intended to look and function as a normal cell but somewhere along the line the genetic "wiring" got crossed and instead of simply dying as it should have done, it divided and produced offspring cells that shared the same mutation as the original parent cell) in some respects - often it becomes more resistant to therapy than the primary (original) tumor - but fundamentally, it remains the same tumor-type.

In other words, a rectal cancer in the lung remains rectal cancer. The cell has identifiable characteristics which usually allow the pathologist to determine its point of origin. In fact, sometimes in cancer, a primary tumor never is located but the metastatic cells can be identified as having come from a specific organ system because of the way they look and because they express certain molecules which can be identified chemically.

Therefore, the treatment for a breast cancer, for example, that has metastasized to a different part of the body generally is treated in a similar manner as if the tumor cells all were contained within the region of the breast.

However, from the viewpoint of assay-directed therapy, none of that matters because it doesn't necessarily treat all breast cancers with "the" breast cancer protocol or all rectal cancers with "the" rectal cancer protocol (even if there were only one - in fact, there are several protocols to choose from).

Instead, the whole point of functional tumor cell profiling is to determine, individually - that is, for each patient - precisely which drug or drugs is best able to kill that patient's own cancer cells - no matter which drug that happens to be and no matter what type of cancer it is.

If you visit the National Cancer Institute website, you'll see that for virtually all cancers, there is no single "best" regimen listed. Instead, you'll find that, for each cancer type, many drugs and drug combinations have been proven in clinical trails to produce about the same result among large groups of unselected patients.

However, looking at the individual patients within a clinical trial, all of whom have the same type and stage of cancer, some patients do not respond at all to a specific treatment while others respond very well and, even in some of the very difficult cancer types, some patients achieve long-term remissions and even cures.

What this suggests is, considering that there are many drug regimens which are equally-accepted by the NCI and by oncologists, these drugs regimens should not be administered blindly but rather each patient's cancer cells should be tested to determine which of the otherwise equally-acceptable drug regimen has the very best chance of benefiting that particular patient.